Metal complexes of hydrazide-hydrazones and process for producing the same



United States Patent METAL COMPLEXES 0F HYDRAZIDE-HYDRA- ZONES AND PROCESS FOR PRODUCING THE SAL IE Siegfried Petersen, Leverkusen-Schiebusch, Otto Bayer,

Leverkusen-Bayerwerk, Hans A. (life, Leverkusen- Wiesdorf, and Gerhard Domagk, Wuppertal-Elberfeld, Germany, assignors to Schenley Industries, Inc., New York, N. Y., a corporation of Delaware No Drawing. Application October 6, 1953, Serial No. 384,524

Claims priority, application Germany October 9, 1952 11 Claims. (Cl. 260-270) The present invention relates to metal complexes of hydrazones of hydrazides of heterocyclic carboxylic acids, the metal of which is selected from the 2d to the 8th groups of the periodic system and a valence of which is bound. to oxygen, together with procedure for producing such complexes.

It ts known that the hydrazides of heterocyclic car- 7 boxylic acids and hydrazones prepared by the reaction of such hydrazides with aldehydes and ketones are of therapeutic significance and, in particular, that such derivatives of isonicotinic acid have been found to be effective for combatting tuberculosis in humans and animals. It is further known that hydrazides are capable of forming complexes with heavy metals and that in forming such complexes the hydrazides exert a reducing effect on the complex-forming metals at elevated temperature.

Copper complexes of hydrazones of isocyclic carboxylic acid hydrazides (Buu-Hoi, et al., Comptes Rendues 235: 330, 1952) have been prepared but the reaction was found by them to be specific for copper only and the resulting copper complexes have only slight therapeutic usefulness.

We have now found that new and highly useful complexes are obtained when hydrazones of hydrazides of heterocyclic carboxylic acids containing a hetero-atom selected from the group consisting of nitrogen, oxygen and sulfur are reacted with complex-forming metallic compounds of metals of the 2d to 8th groups of the periodic system. The discovery that the above metal complexes can be formed with ease and have new and valuable properties was surprising in view-of the data presented in the literature, particularly because it was entirely unpredictable that the above metal complexes 0 wouldexercise high therapeutic effects since the prevailing view is that the action of isonicotinic acid hydrazide and other tuberculostatic substances is due to the fact that metal is deemed to be withdrawn from the enzymatic system of the tuberculosis bacilli. It is, therefore, surprising that our new metal complexes have excellent tuberculostatic and veterinary utility. Our new compounds,

furthermore, in many cases, represent a marked change -in solubility characteristics and thus, in accordance with acid and pyrimidinecarboxylic acids. The heterocyclic.

2,801,246 Patented July 30, 1957 wherein Me represents the metal, R is the residue of the heterocyclic carboxylic acid, X is any organic residue and Y is selected from the group consisting of hydrogen and an organic residue.

It has been particularly found by us that exceptionally stable, useful and desirable metal complexes of hydrazidehydrazones are obtained when the hydrazide-hydrazones are derived from aldehydes and ketones which bear in the 2-position to the oxy group a substituent capable of participating in the complex formation. Aldehydes and ketones meeting this requirement are, for example, o-oxybenzaldehyde and its derivatives, 2-naphthol-1-aldehyde, 'o-amin'obenzaldehyde, pyridine-Z-aldehyde, pyrrole- 2-aldehyde, furfural, resorcylaldehyde, phthalaldehyde acid, resacetophenone, o-quinones of all types, glycol aldehyde, dextrose, glycerin aldehyde, glyoxalic acid and diacetylmonoxime. Products of bilateral reaction of such o-dioxy' compounds as glyoxal and diacetyl with the hydrazides of heterocyclic carboxylic acids are also elfective and utilizable and constitute a part of the foregoing group. In this case the second hydrazide-hydrazone group serves as the substituent which can take part in the complex formation.

The resulting metal complexes which are generally characterized by exceptional stability have a somewhat different structure and such, in the case of the salicylaldehyde, may be represented by the following type formula:

Me-O

wherein R and Me have the same meanings as hereinbefore stated.

The known copper complexes which have been used primarily for analytical purposes are greatly surpassed in physiologicaleifect and activity by many of our new compounds. Complexes of zinc, aluminum, cobalt, nickel, manganese, vanadium, antimony and iron have been found to be readily prepared in accordance with the invention, the iron complexes being particularly valuable and useful.

The reaction of hydraz'ide-hydrazones with iron compounds to produce Type I complexes results in complexes of bivalent iron but analogous iron complexes of hydrazide-hydrazones of Type I also form when trivalent iron compounds are employed as the complex-forming substances. Type II complexes with trivalent iron compounds are very readily formed and when iron salts sucha s those hereinafter specified are utilized complexes are obtained having the anion of the particular iron salt which is employed for complex-formingpurposes. .However, we have found that complexes can also be formed with iron compounds which do not possess an anion and, therefore,

the invention includes the use of complex-forming organic I metal compounds such as iron butylate, iron acetyl 3 acetonate, iron alcoholates and the like. Analogous conditions exist in connection with the use of other metals of groups 2-8 of the periodic system. In producing complexes for pharmaceutical use, we select metals of a type which are satisfactorily tolerated by the organism, preferably a metal such as iron, the iron complexes of which have been found to be of exceptional activity and value.

The reactions of the hydrazide-hydrazones with the metallic compounds may be effected in water or in a suitable organic solvent, such as an alcohol. By properly selecting the reaction conditions, compounds with oxy, oxo or basic groups, such as pyridine, may beincorporated into the complexes as attachments and'in some instances complex formation can be achieved merely by grinding or triturating the metal saltor other metal compound with the hydrazide-hydrazone.

Our new complexes are generally characterized by exceptional or good stability, acceptable non-toxicity, high therapeutic activity and, in many cases, by a marked change in solubility characteristics as compared with the hydrazide-hydrazones themselves and the previously knowncopper complexes. ble, in accordance with the invention, to prepare easily administerable, water-soluble metal complexes, particularly in the case of aluminum and iron complexes, from hydrazide-hydrazones which are water-insoluble.-

The following examples illustrate the invention withoutlimiting it thereto:

Exaniple 1 482 gm. (approximately 1 mol) of ferric ammonium sulfate NH4Fe (SO4)z'12HzO, is finely pulverized. To this 2.41 gm. of o-oxy-benzalisonicotinic acid hydrazide are, addedin the form of fine powder. The two componentsare ground in a ball mill for 1 hour. In this manner brownish-black conglomerated lumps are obtained whichdisintegrate in water. up in 5 liters of water, stirred for some time at 70 C., and then the resultantiron complex filtered off. This is washed with water to complete neutrality, washed with alcohol, and dried at 50 C. There results 396 gm. of a heavy olive-brown powder the analytic composition of which corresponds to the formula C13H1oO2N3FeSO4 2H2O which may be represented as:

I e-O This product has been found to be particularly valuable for veterinary use,

Example 2 (a) 20 gm. of sublimed ferric chloride are dissolved in 200 cc. of methanol, ethanol or butanol. To this 24.1 gm. of moxy-benzalisonicotinic acid hydrazide are added. The material immediately takes on a dark-green color which crystallizes without solvent. The mixture is main- (b) Fural-isonicotinic acid hydrazide, in equivalent proportions based on Example 2a, can be reacted in analogous fashion. In this case the hydrazide-hydrazone initially dissolves with an olive-green color but precipitates after about 15 minutes in voluminous crystals, which Thus, it is frequently possi- This mass is taken a are filtered off by vacuum filtration after another half-hour and washed with methanol and ethanol.

Example 3 Anhydrous iron chloride FeCla is dissolved in butanol, diluted with benzene, and ammonia is introduced into this solution until its reaction is weakly alkaline. Upon removal of the resultant ammonium chloride by vacuum filtration, there remains a brown solution of iron butylate, which is concentrated by distillation of the solvent. 30 cc. of this solution, which contains about 26% FeaOa, are added to a suspension of 12 gm. of o-oxy-benzalisonicotinic acid hydrazide. As a result, the charge is immediately discolored to an intense olive-green hue. It is now boiled under reflux for about 1 hour. The resultant product is filtered oif by vacuum filtration and washed with alcohol and ether. The iron complex is a lowweight powder of olive-brown-greenish color. It is fairly soluble in alcohol. The product may be represented by the following approximate formula:

Analogous results are produced by using iron acetyl acetonate or other non-ionic metal compounds instead of iron butylate.

Example 4 gm. of aluminum sulfate (or an equivalent amount ofpotassium aluminum sulfate) are dissolved in 400 cc. of water. To this solution 24.1 gm. of o-oxy-benzalisonicotinic acid hydrazide are added, followed by brief boiling. The major portion of the material goes into solution. After being cooled to 45-50 C., the yellow. solution isfiltered and subsequently cooled intensively. Fine dark-yellow needles of the aluminum complex. precipitate. The complex is soluble in water and methanol. It is washed with a small amount of ice water, acetone and ether. Upon drying under heat the complex assumes an orange-red color without becoming water-insoluble. The formula is analogous to that of Examplel with aluminum replacing iron. Aluminum chloride- AlCls in alcoholic solution produced results analogous to Example 2a with aluminum replacing iron in. the formula and this complex could only be recovered by concentration of its solution. It is sparingly soluble in; alcohol. Complexes were also formed through the use; of, aluminum butylate and aluminum acetoacetic ester when dissolvedin toluene. These solutions exhibit a-unique, type of fluorescence of striking greenish-yellow n'q l lle.v The;a queous solutions of the metal salt complexes also fluoresce.

An alcoholic solution of cerium chloride CeCla forms a cerium complex. with o-oxybenzal-isonicotinic acid hydrazide and after boiling for 1 hour the complex precipitates as a yellowish-red powder.

Example 5 25. gm. of crystallized cobaltous chloride are dissolved in 250 cc. of methanol, and subsequently 12 gm. of o-oxy-benzalisonicotinic acid hydrazide are introduced in finely pulverized form. The material dissolves at 30 C. with agreen color. Now a current of air is passed through the solution for several hours, with the result that a brown complex, presumably derived from trivalent cobalt, slowly precipitates. This is washed with alcohol and dried under heat.

Example 6 A yellow manganese complex was formed from a cold alcoholic solution of manganous chloride with o-oxybenzalisonicotinic acid hydrazide. This complex, upon prolonged boiling, was converted to a dark-brown color and crystallized in needles. The yellow complex contains 2 chlorine atoms to 1 of the o-oxybenzal-isonicotinic acid hydrazide whereas the dark-brown complex was found to have a lower chlorine content.

Example 7 A dilute aqueous solution of ammonium vanadate (NI-I4)4V4O1z and o-oxybenzal-isonicotinic acid hydrazide formed a yellow solution from which, after cooling, there were precipitated yellow needles of the vanadium complex which may be represented by the formula:

Example 8 A methanol solution of antimony trichloride immediately formed an orange-colored complex with o-oxybenzal-isonicotinic acid hydrazide containing about 2.7 atoms of chlorine to 3 atoms of nitrogen (1 mol of o-oxybenzalisonicotinic acid hydrazide). This complex was found to be highly effective against tuberculosis (1: 10,000,000) but is not tolerated by the animal organism as well as the iron complexes.

Example 9 23 gm. of o-oxy-pyromucic acid hydrazide are introduced into a solution of 20 gm. of anhydrous iron chloride FeCla in 200 cc. of alcohol. The material immediately goes into a dark olive-green solution, but reprecipitate's in the form of a voluminous, nearly black, crystallized mass after about 15 minutes of heating. After boiling for 1 hour, it is filtered off by vacuum filtration and washed with alcohol. The yield amounts to 24.5 gm. of the iron complex of the above compound.

Example 10 A solution of 27.2 gm. of anhydrous zinc chloride in 150 cc. methanol is added to a suspension of 24.1 gm. of o-oxy-benzal-isonicotinic acid hydrazide'in l00cc. methanol. The precipitate thus formed immediately takes on a brilliant yellow-color. While boiling under reflux for half an hour, the charge slowly thickens. It is filtered oil? by vacuum filtration and thoroughly washed with alcohol and ether. The dried zinc complex represents a yellow powder which is difficultly soluble in water. It contains, by analysis, 4 mols of o-oxybenzal-isonicotinic acid hydrazide to 3 mols of ZnClz. Its therapeutic eifects are similar to the complex of Example 3.

Example 11 (a) gm. of hydrated nickelous chloride are dissolved with heating in 200 cc. of alcohol and this green solution is added slowly to a suspension of 13.7 gm. of the hydrazone of isonicotinic acid hydrazide and 2-hydroxynaphthaldehyde-l (l-formyl 2 hydroxynaphthalene) in 100 cc. of alcohol. The mixture immediately assumes a reddish-brown color. It is boiled under reflux for some time, followed by vacuum filtration at elevated temperature and washing with alcohol. Drying yields 20.5 gm. of a brownish-red nickel complex which is sparingly soluble in alcohol.

(b) In analogous fashion nickelous chloride in alcoholic solution can be reacted with o-oxy-benzal-isonicotinic acid hydrazide or with (c) o-Oxy-benzal-pyromucic acid hydrazide in equivalent proportions based on Example 11(a) to provide the corresponding hydrazide-hydrazone nickel complexes.

Example 12 22.5 gm. of benzal-isonicotinic acid hydrazide are slowly added to a solution of gm. of sublimed iron chloride in 200 cc. of methanol. The compound goes into olive-green solution. This is accompanied by slight evolution of gas. After being filtered to clarity, the solu- Example 13 16.2 gm. of the bilateral reaction product of diacetyl and isonicotinic acid hydrazide are suspended in 100 cc. of methanol. To this is added a solution of 32.4 gm. of anhydrous iron chloride in 150 cc. methanol, and the mixture is heated under reflux for 1 hour. The resultant dark compound is then filtered oil by vacuum filtration under heat and washed with methanol and ether. It does not melt below 300 C. and is readily soluble in water.

By contrast, the starting material scarcely dissolves in water.

Example 14 (a) 12.8 gm. of the reaction product of resorcylaldehyde and isonicotinic acid hydrazide are suspended in 20 cc. of alcohol. After addition of a solution of 10 gm. of iron chloride FeCls in cc. alcohol all the components dissolve. However, heating under reflux results in the formation of crystals, which are filtered off by vacuum after 1 hour and washed with alcohol. The yield is 17 gm. of iron complex.

(b) In analogous fashion, proportional amounts of the r reaction products of 2-oxy-3-methoxybenzaldehyde or of (c) 2-oxy 4 methoxybenzaldehyde with isonicotinic acid hydrazide can be converted into the corresponding dark-colored iron complexes by means of anhydrous iron chloride FeCla dissolved in methanol, ethanol, or butanol.

The foregoing is presented as illustrative and exemplary and not as limitative or restrictive since other, similar or analogous metallic complexes can be produced while still adhering to the principles of the invention. For instance, other o-oxybenzal compounds or derivatives may be employed for metal complex formation in accordance with the invention such as 3,5-dichloro-2-oxybenzaldehyde, 6-nitro-2-oxynaphthaldehyde,, 2-oxy-naphthaldehyde and 2,4-dioxyacetophenone. In the case of the 2,4-dioxyacetophenone compound, there was produced of melting point 270-272 C. which yieldeda greenish black iron complex with FeCla having the formula:

thus at the same time confirming the general formula for this type of ketone derivative.

The compound:

Thiscompoundhasbeen found to have ananti-streptococcal efiectas-well as good.antitubercularelficacy. i

Our invention, therefore, is directed to new metalcom: plexes, particularly of hydrazide-hydrazones, thisterm being employedin the present specification and claims to designate vhydrazonesawhich are. .derived. from hydrazides as distinguishedfrom hydrazides themselves and .from hydrazones which are derived from. hydrazines. The metal. lHithelIOHlPlCXdS, in particular, selected from the group particularly consistingofairon; aluminum, cobalt, zinc, manganese, vanadium, antimony and nickel but includes all metals falling within" groups 2 to 8 of the periodic system;which arenon-toxic; andhave therapeutic activity or whichsmaysbeemployediin the synthesis or preparationofxelated. orderivative compounds and complexes. Frorn:therab.o.veexamplesitwill be understood that .the.n1etal compounds.are;.preferably, although not necessarily, metal saltswherein theanion is sulphate or chloride and.wherein thepmetal. may bev either in the ous or ic condition for. those metals which, like, iron and nickel, form ferrous and ferric and. nickelous and nickelic compounds, respectively. As explained above, however, metal compounds may be employed which have no anion and which are non-ionic and wherein the metal is combined with an organic radical, such as butylate, acetyl acetonate oranalc'oholate. Itis also to be understood that the metal. compounds-e. g., the inorganic metal salts involvedrnay be in either an anhydrous or a hydrated condition, especially where a water solution there of is employed, and that where'a metal forms salts of different degrees of hydration, such as, for example, aluminum sulfate, any of the various hydrated metal salts may ordinarily be employed in the invention by adjusting the quantity utilized so that the appropriate amount of the metal is present. In general, We have found that the molecular ratio between the hydrazone and the metal lic atomin the complex ranges-from approximately 1:1 to approximately 1:4, as can be calculated from the foregoing examples. The invention also includes the process for making our new metal complexes by procedure such as that described above. The invention is more particularly defined by the appended claims.

We claim: 1. A metal complex of a hydrazone of a hydrazide of a heterocyclic carboxylic acid selected from the group consisting of nicotinic acid, isonicotinic acid and pyromucic acid, and a compound of a metal selected from the group consisting of iron, aluminum, cobalt; zinc, manganese, vanadium, antimony and nickel.

2. A process for. producingametal complex'defined.

by claim 1, which'comprises reacting a hydrazone of a hydrazide of a heterocycliccarboxylic acid selected from the group consisting, ofgnicotinic acid, isonicotinic acid andpyromucicl acidiwith. a compound ot a metal. selected.

from thegroupconsistingof iron, aluminum, cobalt, manganese,.zinc, vanadium, antimony and nickel.

3. The metal. complexreaction .productof o-oxyb'enr.

zalisonicotinic acid hydrazide and ammonium iron alum.

4. The metal complex reaction product .of o-oxy-benzalisonicotinic acidhydrazide and ferric chloride.

5. The metal complex reaction product of furalisonicotinic acid hydrazideand ferric chloride.

6. The metal complex reaction product of benzal-isonicotinic acid hydrazide, and: iron chloride? 7. The metal complexireaction product of ironchloride: with the product of reaction of'2-oxy 3-methoxybenzalde1,

hyde and isonicotinic acid hydrazide.

8. A process-aim accordance with .claim 2 whereinthe reaction is carriedout with an aqueous solution of a watersoluble metallic compound;

9. A process in accordance with claim 2 wherein-thereaction is carried out with a. solution of the metallic compound in anorganic solvent.

10. A process in accordance with claim 9 wherein the organic solvent is an alcohol.

11. A process in accordance withclairn .2 wherein the metal compound is a salt and, is .ground with the hydrazone'to form the complex.

References Cited in the file of this patent FOREIGN PATENTS 219,801 Switzerland June 16, 1942 OTHER REFERENCES 

1. A METAL COMPLEX OF A HYDRAZONE OF A HYDRAZIDE OF A HETEROCYCLIC CARBOXYLIC ACID SELECTED FROM THE GROUP CONSISTING OF NICOTINIC ACID, ISONICOTINIC ACID AND PYROMUCIC ACID, AND A COMPOUND OF A METAL SELECTED FROM THE GROUP CONSISTING OF IRON, ALUMINUM , COBALT, ZINC, MANGANESE, VANADIUM, ANTIMONY AND NICKEL. 